Tumorigenicity-associated characteristics of human iPS cell lines

Satoshi Yasuda, Shinji Kusakawa, Takuya Kuroda, Takumi Miura, Keiko Tano, Nozomi Takada, Satoko Matsuyama, Akifumi Matsuyama, Michiyo Nasu, Akihiro Umezawa, Takao Hayakawa, Hideki Tsutsumi, Yoji Sato

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12 Citations (Scopus)

Abstract

Human induced pluripotent stem cells (hiPSCs) represent promising raw materials of human cell-based therapeutic products (hCTPs). As undifferentiated hiPSCs exhibit intrinsic tumorigenicity properties that enable them to form teratomas, hCTPs containing residual undifferentiated hiPSCs may cause tumor formation following transplantation. We first established quantitative and sensitive tumorigenicity testing of hiPSCs dissociated into single cells using NOD/Shi-scid IL2Rγnull (NOG) mice by inhibiting apoptosis of hiPSCs with a Rho kinase inhibitor. To examine different features in tumorigenicity of various hiPSCs, 10 commonly available hiPSC lines were subjected to in vivo tumorigenicity testing. Transplanted hiPSC lines showed remarkable variation in tumor incidence, formation latency, and volumes. Most of the tumors formed were classified as immature teratomas. However, no signs of malignancies, such as carcinoma and sarcoma, were recognized in the tumors. Characteristics associated tumorigenicity of hiPSCs were investigated with microarray analysis, karyotype analysis, and whole exome sequencing. Gene expression profiling and pathway analysis supported different features of hiPSC lines in tumorigenicity. hiPSC lines showed chromosomal abnormalities in some lines and 61±77 variants of cancer-related genes carrying effective nonsynonymous mutations, which were confirmed in the COSMIC databases. In this study, the chromosomal abnormalities and cancer-related gene mutations observed in hiPSC lines did not lead to the malignancy of tumors derived from hiPSCs. Our results suggest that the potential tumorigenicity risk of hCTPs containing residual undifferentiated hiPSCs is dependent on not only amounts of undifferentiated hiPSCs but also features of the cell lines used as raw materials, a finding that should be considered from the perspective of quality of hCTPs used.

Original languageEnglish
Article numbere0205022
JournalPloS one
Volume13
Issue number10
DOIs
Publication statusPublished - 10-2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Yasuda, S., Kusakawa, S., Kuroda, T., Miura, T., Tano, K., Takada, N., Matsuyama, S., Matsuyama, A., Nasu, M., Umezawa, A., Hayakawa, T., Tsutsumi, H., & Sato, Y. (2018). Tumorigenicity-associated characteristics of human iPS cell lines. PloS one, 13(10), [e0205022]. https://doi.org/10.1371/journal.pone.0205022